3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate, process for production of the same, and use of the same

ABSTRACT

The present invention provides 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a C 1-6  alkyl group, etc., R 2  is a hydrogen atom or a COOR 3  group, wherein R 3  is a tert-C 4-6  alkyl group, a 2,2,2-trichloroethyl group or a benzyl group in which the benzene ring moiety may be optionally substituted by one or two atoms or groups independently selected from the group consisting of a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a cyano group and a nitro group, and a salt thereof, which are useful as a novel intermediate for preparing tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and the process for preparing the same.

TECHNICAL FIELD

This invention relates to a novel3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate useful as an intermediateof active pharmaceutical ingredient of a therapeutic agent for diabeticcomplications, etc., and a process for preparing the same, as well as aprocess for preparing Ranirestat being useful as a therapeutic agent fordiabetic complications using the intermediate.

BACKGROUND ART

Tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives whichare promising therapeutic agents for diabetic complications showing apotent aldose reductase inhibitory activity are disclosed in theliterature (for example, see JP-A-5-186472; and J. Med. Chem., 1998, 41,p. 4118 to 4129). Also Ranirestat [AS-3201;(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidin-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone] selected among these derivatives has beendeveloped clinically. 3-Amino-2,5-dioxopyrrolidine-3-carboxylates aredisclosed as the intermediate suitable to prepare these derivatives onthe industrial scale in the literature (for example, see JP-A-6-192222),and the process for preparing the same is also disclosed in theliteratures (for example, JP-A-5-186472, JP-A-6-192222 and J. Med.Chem., 1998, 41, p. 4118 to 4129 as aforementioned). The summary of theprocess for preparing the same is illustrated in following Scheme 1.

wherein R¹ and R⁶ are a protecting group for a carboxyl group, R⁴ is agroup cleavable by hydrogenolysis or a tert-butoxycarbonyl group, R⁵ isa tert-butyl group or a group cleavable by hydrolysis or hydrogenolysis.

In the above route A and route B, there is a step for a ring closurereaction of the 3-cyanopropionic acid ester moiety using hydrogenperoxide and base to form 2,5-dioxopyrrolidine ring and then it isdifficult for this step to control the reaction temperature. This iscaused by the fact that this step is an exothermic reaction and thusoften happens to foam violently. Therefore it is necessary to proceedwith this step while cooling. But excess cooling makes the progress ofthe reaction insufficient to complete and results in lowering the yieldand the purity of the desired product. On the other hand, insufficientcooling results in forming a large amount of side products and thussimilarly as above, results in lowering the yield and the purity of thedesired product. Therefore it is necessary to improve this step. Alsorelatively high level of hydrogen peroxide used in this step isdangerous and thus there is a risk of decomposing violently in thereaction. Therefore it is also desirous of a method for avoiding the usethereof.

The route C is the process without use of hydrogen peroxide. But it isdesirous of a more economically advantageous method since this routerequires a large number of steps in total compared to the route A andthe process shown in Scheme 2 mentioned below.

A literature describes a preparation of2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide by reacting diethylbenzyloxycarbonylaminomalonate with sodium hydride and bromoacetamide inthe examples (see JP-A-6-192222). But this process is not preferred forthe industrial scale preparation because of low yield (36.5%) as well asevolution of hydrogen gas in the course of the reaction with sodiumhydride.

DISCLOSURE OF INVENTION Problems to be Solved by Invention

An object of the present invention is to provide a process for preparingactive pharmaceutical ingredient oftetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives (forexample, Ranirestat) which are promising therapeutic agents for diabeticcomplications in a short process and in an economically advantageous andsafe manner. Specifically, an object of the present invention is toprovide a process for preparing3-amino-2,5-dioxopyrrolidine-3-carboxylates as an intermediate usefulfor active pharmaceutical ingredient without use of hydrogen peroxideand in a short process and in an economically advantageous manner.

Means for Solving Problem

The present inventor has intensively studied in order to achieve theabove-mentioned objects, and has found that3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates can be prepared from2,5-dioxopyrrolidine-3-carboxylates in one step, conveniently and inhigh yields, and further the3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates can be converted into3-amino-2,5-dioxopyrrolidine-3-carboxylates in one or two steps,conveniently and in high yields, and has accomplished the presentinvention. That is, the present invention provides novel3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates and salts thereof(hereinafter abbreviated as the compound of the invention) useful as anintermediate for tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidinederivatives, etc.

That is, the present invention relates to the following embodiments:

[1] 3-Hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (I):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group;

R² is a hydrogen atom or a COORS group;

wherein when R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkylgroup; a C₃₋₄₃ cycloalkyl group; or an aryl group or a heteroaryl groupoptionally substituted by one or two groups independently selected fromthe group consisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, thenR³ is a tert-C₄₋₆ alkyl group; a 2,2,2-trichloroethyl group; or a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, acyano group and a nitro group;

when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group;

when R¹ is a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group and a cyano group, then R³ is a tert-C₄₋₆alkyl group or a 2,2,2-trichloroethyl group, or a salt thereof.

[2] The 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as set forth in[1] wherein R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkyl group,R² is a hydrogen atom or a COORS group, and R³ is a tert-C₄₋₆ alkylgroup or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group, or a saltthereof.[3] The 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as set forth in[1] wherein R¹ is a methyl group, an ethyl group, a propyl group or anisopropyl group, and R² is a hydrogen atom, a tert-butoxycarbonyl groupor a benzyloxycarbonyl group, or a salt thereof.[4] The 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as set forth in[1] selected from the group consisting of

-   ethyl    3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,-   ethyl    3-[N,N′-bis(tert-butoxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,    and-   ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate    monohydrochloride,    or a salt thereof.

The present invention provides the process for preparing the novel3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as follows:

[5] A process for preparing

3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (Ia):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group;

wherein when R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkylgroup; a C₃₋₈ cycloalkyl group; or an aryl group or a heteroaryl groupoptionally substituted by one or two groups independently selected fromthe group consisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, thenR³ is a tert-C₄₋₆ alkyl group; a 2,2,2-trichloroethyl group; or a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, acyano group and a nitro group;

when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group;

when R¹ is a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group and a cyano group, then R³ is a tert-C₄₋₆alkyl group or a 2,2,2-trichloroethyl group,

comprising the step of adding the compound of the formula (III):

R³OOC—N═N—COOR³  (III)

wherein R³ is as defined above,to the compound of the formula (II):

wherein R¹ is as defined above.[6] A process for preparing3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (Ib):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group,comprising the following steps:(1) a step of undergoing a hydrogenolysis of the compound of the formula(Ia) as set forth in [5] wherein R³ is a benzyl group in which thebenzene ring moiety may be optionally substituted by one or two atoms orgroups independently selected from the group consisting of a halogenatom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitrogroup in the presence of a palladium catalyst;(2) a step of reacting the compound of the formula (Ia) as set forth in[5] wherein R³ is a tert-C₄₋₆ alkyl group with an acid; or(3) a step of reacting the compound of the formula (Ia) as set forth in[5] wherein R³ is a 2,2,2-trichloroethyl group with zinc.

The present invention provides the novel process for preparing the3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates using the compound ofthe formula (I) as a starting material as follows:

[7] A process for preparing the compound of the formula (IV):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group,by using the formula (Ic):

wherein R¹ is as defined above; and R²¹ is a hydrogen atom or a COOR³¹group;

wherein R³¹ is a 2,2,2-trichloroethyl group or a benzyl group in whichthe benzene ring moiety may be optionally substituted by one or twoatoms or groups independently selected from the group consisting of ahalogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group anda nitro group,

comprising the following step:a step of reacting the compound of the formula (Ic) wherein R²¹ is ahydrogen atom or a COOR³¹ group, wherein R³¹ is a 2,2,2-trichloroethylgroup with zinc; ora step of undergoing a hydrogenolysis of the compound of the formula(Ic) wherein R²¹ is a hydrogen atom or a COOR³¹ group, wherein R³¹ is abenzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a cyano group and a nitro group (with the proviso thatexcept the compound wherein R¹ is a benzyl group in which the benzenering moiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group and a cyano group).[8] The present invention provides a novel process for preparing2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising the step of preparing the compound of the formula (I) as setforth in [1]by the process as set forth in [5] or [6], and the step ofconverting the compound of the formula (I) into2′-(4-bromo-2-fluorobenzyl)spiro-[pyrrolidine-3,4(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3 ′,5(2H′)-tetraone.[9] The present invention provides the use of the compound of theformula (I) as set forth in [1] in the manufacture of2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone.[10] A use of 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as setforth in any one of [1] to [4] or a salt thereof in the manufacture of amedicament.[11] The use of 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as setforth in any one of [1] to [4] or a salt thereof in the manufacture of(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone.

The present invention provides the novel process for preparing the(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone as follows:

[12] A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone, comprising using3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as set forth in any oneof [1] to [4] or a salt thereof as an intermediate or a startingmaterial.

S[13] The process as set forth in [12], characterized by preparing3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates as set forth in any oneof [1] to [4] or a salt thereof by the process as set forth in [5] or[6].

[14] A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1H′)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone, comprising a step of preparing thecompound of the formula (IV) as set forth in [7] and the step ofconverting the compound of the formula (IV) prepared in preceding stepinto(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone.[15] A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone, comprising the following steps:(1) a step of preparing the compound of the formula (IV) as set forth in[7];(2) a step of performing an optical resolution of the compound of theformula (IV) prepared in the above step (1);(3) a step of converting an amino group of the optically active compoundprepared in the above step (2) (wherein the absolute configuration atcarbon atom on 3 position of the dioxopyrrolidine ring of said compoundis R) into 1-pyrrolyl group;(4) a step of converting the pyrrolyl group of the product of the abovestep (3) into 2-trichloroacetylpyrrol-1-yl group; and(5) a step of reacting the product of the above step (4) with4-bromo-2-fluorobenzylamine to convert it into(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone.

Effect of the Invention

The compound of the present invention and the process for preparing thesame can be used to prepare 3-amino-2,5-dioxopyrrolidine-3-carboxylatesbeing useful as active pharmaceutical ingredient and an intermediate forpreparing Ranirestat, etc., which are promising therapeutic agents fordiabetic complications in a short process and in a safe and efficientmanner.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention is explained in more detail below.

The salt of the compound represented by the formula (I) includes thesalt of the compound of the formula (I) having the acidity or basicitysufficient to form a salt, for example, a salt with an alkali metal oran alkaline earth metal such as sodium, potassium or calcium, etc.; asalt with an organic base such as pyridine, triethylamine,diisopropylamine, dicyclohexylamine, etc.; a salt with amino acid suchas lysine, arginine, glutamic acid or aspartic acid, etc.; a salt withinorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid or phosphoric acid, etc.; or a salt with an organicacid such as oxalic acid, malonic acid, maleic acid, fumaric acid,lactic acid, malic acid, citric acid, tartaric acid, trifluoroaceticacid, methanesulfonic acid, p-toluenesulfonic acid ortrifluoromethanesulfonic acid, etc.

The compound of the formula (I) and a salt thereof may exist in ahydrate and/or a solvate form, thus these hydrates and/or solvates arealso included in the compound of the invention. Also the compound of theformula (I) has one more than asymmetric carbon atom, thus it can existin several stereoisomer forms. These stereoisomers and a mixture and aracemate thereof are also included in the compound of the invention.

The terms used herein are explained as follows. Unless definedotherwise, the definition for each group shall also be applied to wheresaid group is a part of another group.

The “C₁₋₆alkyl group” is a straight chain or branched chain alkyl grouphaving 1 to 6 carbon atoms, specifically such as methyl group, ethylgroup, propyl group, isopropyl group, butyl group, isobutyl group,tert-butyl group, pentyl group, isopentyl group, neopentyl group andhexyl group, etc.

The “tert-C₄₋₆alkyl group” is a tert-butyl group optionally substitutedby one to two methyl groups or one ethyl group, specifically such astert-butyl group and tert-pentyl group, etc.

The specific example of “C₁₋₄ alkyl group” includes, for example, methylgroup, ethyl group, propyl group, isopropyl group, n-butyl group,isobutyl group and tert-butyl group, etc.

The “C₃₋₈ cycloalkyl group” is a cyclic alkyl group having 3 to 8 carbonatoms, specifically such as cyclopropyl group, cyclobutyl group,cyclopentyl group and cyclohexyl group, etc.

The “C₁₋₄ alkoxy group” may be a straight chain or branched chain,specifically such as methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group andtert-butoxy group, etc.

The “aryl group” includes a fused polycyclic aromatic hydrocarbon groupcontaining phenyl group or benzene ring, specifically such as phenylgroup and naphthyl group, etc., and preferred specific example includesphenyl group.

The “heteroaryl group” includes a heteroaryl group in which 1 to 4carbon atoms on a 5- to 6-membered monocyclic unsaturated hydrocarbongroup or a polycyclic unsaturated hydrocarbon group fused thereto arereplaced by heteroatom selected from the group consisting of N, O and Satoms, specifically such as pyridyl group, furyl group and thienylgroup, etc.

A specific example of the “benzyl group in which the benzene ring moietymay be optionally substituted by a halogen atom, a C₁₋₄ alkyl group, aC₁₋₄ alkoxy group, a cyano group or a nitro group” includes, forexample, benzyl group, 4-chlorobenzyl group, 3-bromobenzyl group,4-methylbenzyl group, 3-methylbenzyl group, 2-methoxybenzyl group,4-methoxybenzyl group, 4-cyanobenzyl group and 4-nitrobenzyl group, etc.

The “halogen atom” is fluorine atom, chlorine atom, bromine atom andiodine atom.

A specific example of “acid” includes, for example, an inorganic acidsuch as hydrogen chloride, hydrogen bromide, hydrogen iodide andsulfuric acid, etc., or an organic acid such as trifluoroacetic acid,methanesulfonic acid and trifluoromethanesulfonic acid, etc., preferablyhydrogen chloride and trifluoroacetic acid.

The process for preparing the compound of the invention is explained asfollows:

The compound of the formula (I) [the compound of the formula (Ia) andthe compound of the formula (Ib) in Scheme 3] can be prepared bycombining the type of a protecting group for a carboxyl group on2,5-dioxopyrrolidine ring with the type of a protecting group for acarboxyl group on a hydrazino group appropriately and for example,according to the step A and step B illustrated in following Scheme 3.

wherein R¹ and R³ are as defined above.

The compound of the formula (Ia) (the compound wherein R² is a COORSgroup in the formula (I)) can be prepared by reacting the compound ofthe formula (II) with the compound of the formula (III) in anappropriate solvent in the presence or absence of a base (step A).

Specific examples of the solvent used in the step A include methanol,ethanol, isopropanol, tert-butanol, ethyl acetate, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide and water,etc., which can be used alone respectively or in a combination of two ormore kinds thereof. The base is not necessarily required in the step A,but a use of the base can proceed with the reaction more efficiently.Specific examples of the base include potassium carbonate, sodiumcarbonate, sodium bicarbonate, triethylamine, pyridine,1,8-diazabicyclo[5.4.0]undeca-7-ene, sodium ethoxide and potassiumtert-butoxide, etc. The amount used of the base is not limitedotherwise, but can be selected from a catalytic amount to an excessamount to those of the compound of the formula (II). The reactiontemperature is usually at 0 to 100° C., preferably 10 to 30° C.

The compound of the formula (II) can be prepared by reacting a diethylmalonate with 2-chloroacetamide in the presence of the base in one stepaccording to a method described in JP-A-60-16989 or a similar methodthereto.

The compound of the formula (III) is either commercially available, orcan be prepared by a method that is well-known (or disclosed) inliteratures or a similar method thereto.

The compound of the formula (Ib) (the compound wherein R² is a hydrogenatom in the formula (I)) can be prepared from the compound of theformula (Ia) by the following three methods (step B).

The first process for step B includes a method of reacting the compoundof the formula (Ia) (with the proviso that except the compound whereinR¹ is tert-C(alkyl group) with an acid in an appropriate solvent.Specific examples of the solvent used in the reaction include ethylacetate, dichloromethane, 1,4-dioxane, acetic acid and water, etc.,which can be used alone respectively or in a combination of two or morekinds thereof. Specific examples of the acid used in the reactioninclude hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuricacid, trifluoroacetic acid, methanesulfonic acid andtrifluoromethanesulfonic acid, etc., with among them hydrogen chlorideor trifluoroacetic acid being preferred. A preferred reactiontemperature is at 0 to 30° C.

The second process for step B includes a method of reacting the compoundof the formula (Ia) wherein R³ is 2,2,2-trichloroethyl group with zincin an appropriate solvent. This process can be carried out according tothe method described in Synthesis, 457 (1976) or a similar methodthereto. Specific examples of the solvent include acetic acid,tetrahydrofuran and water, etc., which can be used alone respectively orin a combination of two or more kinds thereof. Zinc is usually used inan excess amount. The reaction temperature is usually at 10 to 120° C.

The third process for step 13 includes a method of undergoing ahydrogenolysis of the compound of the formula (Ia) wherein R³ is abenzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a cyano group and a nitro group in an appropriate solventin the presence of a catalyst such as palladium carbon ethylenediaminecomplex for a short duration. Specific examples of the solvent includeethyl acetate, methanol, ethanol, isopropanol and tetrahydrofuran, etc.,which can be used alone respectively or in a combination of two or morekinds thereof. A preferred solvent is ethanol. The reaction temperatureis usually at 0 to 80° C. The preferable reaction time is usually 1 to 4hours at room temperature, but which depends on the kind of catalyst, areaction temperature or a manner for stirring, etc.

The compound of the formula (Ic) [the compound of the formula (Ia) orthe compound of the formula (Ib) wherein R³¹ is a benzyl group in whichthe benzene ring moiety may be optionally substituted by one or twoatoms or groups independently selected from the group consisting of ahalogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group anda nitro group) (with the proviso that except the compound wherein R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group)] is decomposed in a catalytichydrogenolysis or a catalytic hydrogen transfer to produce the abovecompound of the formula (IV). The catalytic hydrogenolysis is carriedout in an appropriate solvent under hydrogen at atmospheric pressure orincreased pressure in the presence of a catalyst such aspalladium-carbon, platinum-carbon, platinum oxide and Raney nickel, etc.Specific examples of the solvent include methanol, ethanol, isopropanol,acetic acid and water, etc., which can be used alone respectively or acombination of two or more kinds thereof. When a neutral solvent is usedin the catalytic hydrogenolysis, an acid such as hydrogen chloride ortrifluoroacetic acid, etc., may be added. The reaction temperature isusually at 0 to 80° C. The decomposition by catalytic hydrogen transfercan be carried out according to the method described in J. HeterocyclicChem. 18, 31 (1981) and Indian J. Chem. 42B, 1774 (2003) or a similarmethod thereto. The source of hydrogen used includes, for example,ammonium formate, formic acid, cyclohexene and hydrazine, etc. Specificexamples of the solvent include methanol, ethanol, isopropanol, aceticacid and water, etc., which can be used alone respectively or in acombination of two or more kinds thereof.

The above compound of the formula (Ic) [wherein R³¹ is2,2,2-trichloroethyl group] and the compound of the formula (Ib) can bereacted with zinc in an appropriate solvent according to the methoddescribed in Tetrahedron Lett. 30, 2889 (1989) to give the abovecompound of the formula (IV).

The compound of the formula (I) other than the compound of the formula(Ic) can be used in the preparation of the compound of the formula (Ib).

The compound of the formula (V) [for example, the optical activesubstance of the compound of the formula (IV) wherein R¹ is an ethylgroup (the compound of Example 10 mentioned below)] which can beprepared from the compound of the formula (I) of the present inventionis an intermediate oftetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives (forexample, Ranirestat) which are promising therapeutic agents for diabeticcomplications described in aforementioned JP-A-5-186472 andJP-A-6-192222. Thus the compound of the formula (I) of the presentinvention is applicable as starting material of Ranirestat. AlsoJP-A-08-176105 describes that2-ethoxycarbonyl-2-(2-trichloroacetylpyrrol-1-yl)succinimide, which canbe prepared from the compound of the formula (IV) as a startingmaterial, is an intermediate of 2-carboxysuccinimide derivatives usefulas a therapeutic agent for diabetic complications. The compound of theinvention having a chemically modifiable side chain can become anintermediate or a starting material useful in creating pharmaceuticals,since the 2,5-dioxopyrrolidine skeleton is a chemical structure oftenfound in the substructure of compounds useful as pharmaceuticals such asa therapeutic agent for diabetes-related conditions or a central nervoussystem agents.

EXAMPLES

The present invention is illustrated in more detail below by Examples,but the present invention should not be construed to be limited thereto.The compounds were characterized by proton nuclear magnetic resonancespectrum (¹H NMR), carbon 13 nuclear magnetic resonance spectrum (¹³CNMR), and mass spectrum (MS) analyses. Tetramethyl silane is used as aninternal standard in the nuclear magnetic resonance spectrum analyses.Silica gel was used as a loading material for a flash columnchromatography. For the abbreviations in Examples, Ph is phenyl groupand Bu^(t) is tert-butyl group.

Example 1 Preparation of Ethyl3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate

To a solution of 20% sodium ethoxide-ethanol solution (34.0 g) dilutedwith ethanol (40 ml) was added a solution of diethyl malonate (16.0 g)in ethanol (40 ml) dropwise over 30 minutes in ice-cooling. Afterstirring in ice-cooling for additional 30 minutes, thereto was added2-chloroacetamide (4.7 g) in one portion and the mixture was stirred inice-cooling for 30 minutes and then at room temperature for 20 hours.The white solid precipitated was collected by filtering and washed witha small amount of ethanol. This white solid was dissolved in water (300ml) and this resulting aqueous solution was acidified with conc.hydrochloric acid and extracted with dichloromethane (50 ml) threetimes. The extract was dried over magnesium sulfate, filtered andconcentrated to give a yellow oil. This was purified by a flash columnchromatography (n-hexane:ethyl acetate=2:1→1:1) to give ethyl2,5-dioxopyrrolidine-3-carboxylate (5.63 g, 66%).

¹H NMR (300 MHz, CDCl₃, 23° C.) δ: 4.28 (2H, q, J=7.4 Hz), 3.85 (1H, dd,J=5.0, 9.5 Hz), 3.15 (1H, dd, J=5.0, 18.5 Hz), 2.95 (1H, dd, J=9.3, 18.5Hz), 1.32 (3H, t, J=7.1 Hz). ¹³C NMR (75 MHz, CDCl₃, 24° C.) δ: 175.9,172.7, 167.2, 62.7, 47.7, 33.3, 14.0.

To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (3.92 g) inethyl acetate (60 ml) was added dibenzyl azodicarboxylate (7.27 g),followed by potassium carbonate (317 mg) at room temperature. After thismixture was stirred at room temperature for 1 hour, the mixture wasfiltered through a Celite pad. The filtrate was concentrated and theresulting residue was purified by a flash column chromatography(hexane:ethyl acetate=2:1) to give the desired product (10.1 g, 94%) asamorphous.

¹H NMR (300 MHz, DMSO-d₆, 120° C.) δ: 11.4 (1H, br), 9.66 (1H, br),7.35-7.25 (10H, m), 5.15-5.02 (4H, m), 4.14 (2H, q, J=7.1 Hz), 3.40 (1H,d, J=18.3 Hz), 3.17 (1H, d, J=18.2 Hz), 1.14 (3H, t, J=7.1 Hz).

Example 2 Preparation of ethyl3-amino-2,5-dioxopyrrolidine-3-carboxylate

To a solution of the compound of Example 1 (496 mg) in acetic acid (15ml) was added platinum oxide (102 mg). This mixture was stirredvigorously at 50° C. under hydrogen (atmospheric pressure) for 6 hours.During this reaction, to remove carbon dioxide generated with theprogress of the reaction, the gas in the reactor was replaced withhydrogen gas several times. The reaction mixture was filtered through aCelite pad and then the Celite was washed with a small amount of aceticacid. The filtrate combined with the washers was concentrated and to theresulting residue was added toluene to remove azeotropically theresidual acetic acid and then the mixture was concentrated again. To theresidue was added ethyl acetate and the insoluble material was filteredoff, and then the ethyl acetate solution was concentrated to give acrude product which was then purified by a flash column chromatography(chloroform:methanol=30:1) to give the desired product (126 mg, 64%) ascrystal. ¹H NMR (CDCl₃) data of this product were consistent with thoseof an optical active substance described in J. Med. Chem., 1998, 41, p.4118 to 4129.

¹H NMR (400 MHz, CDCl₃, 22° C.) δ: 4.28 (2H, q, J=7.1 Hz), 3.18 (1H, d,J=18.0 Hz), 2.76 (1H, d, J=18.0 Hz), 1.29 (3H, t, J=7.2 Hz). ¹H NMR (400MHz, THF-d₈, 23° C.) δ: 10.38 (1H, s), 4.18 (2H, q, J=6.7 Hz), 3.07 (1H,d, J=18.0 Hz), 2.57 (1H, d, J=17.6 Hz), 1.22 (3H, t, J=7.2 Hz). ¹³C NMR(100 MHz, THF-d₈, 25° C.) δ: 177.6, 175.6, 171.8, 65.5, 62.8, 43.9,14.4.

Example 3 Preparation of ethyl3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate

To a solution of the compound of Example 1 (1.00 g) in ethanol (30 ml)was added 5% palladium-carbon ethylenediamine complex (100 mg). Themixture was stirred vigorously at room temperature under hydrogen(atmospheric pressure) for 2.5 hours. During this reaction, to removecarbon dioxide generated with the progress of the reaction, the gas inthe reactor was replaced with hydrogen gas several times. The reactionmixture was filtered through a Celite pad and then the Celite was washedwith ethanol. The filtrate combined with the washers was concentrated togive the desired product (432 mg, quantitative) as oil

¹H NMR (300 MHz, DMSO-d₆, 25° C.) δ: 4.16 (2H, q, J=7.1 Hz), 2.96 (1H,d, J=17.8 Hz), 2.86 (1H; d, J=17.9 Hz), 1.18 (3H, t, J=7.1 Hz).

Example 4 Preparation of ethyl 3-[N,N′-bis(tert-butyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate

To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (2.96 g) inethyl acetate (25 ml) was added di-tert-butyl azodicarboxylate (4.19 g),followed by potassium carbonate (4.78 g) at room temperature. After thisreaction mixture was stirred at room temperature for 15 minutes, theresulting mixture was filtered through a Celite pad and the filtrate wasconcentrated. The residue was purified by a flash column chromatography(hexane:ethyl acetate=3:1) to give the desired product (5.77 g, 83%) asamorphous.

¹H NMR (300 MHz, DMSO-d₆, 120° C.) δ: 11.3 (1H, br), 8.80 (1H, br), 4.20(2H, q, J=7.1 Hz), 3.41 (1H, d, J=18.1 Hz), 3.17 (1H, d, J=18.1 Hz),1.41 (9H, s), 1.40 (9H, s), 1.23 (3H, t, J=7.1 Hz).

Example 5 Preparation of ethyl3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate monohydrochloride

To a solution of the compound of Example 4 (5.77 g) in ethyl acetate (20ml) was added a solution of 4M hydrogen chloride in ethyl acetate (25ml) and the mixture was stirred at room temperature for 24 hours. Theresulting precipitates were collected by filtering and washed with ethylacetate to give the desired product (3.02 g, 76%) as powder. The desiredproduct was identified to be a monohydrochloride salt thereof by theresults of elementary analysis and X-ray crystallographic analysis.Melting point: 189-190° C. (decomposition). ¹H NMR (300 MHz, DMSO-d₆,25° C.) δ: 12.1 (1H, br), 9.58 (3H, br), 4.23 (2H, q, J=7.0 Hz), 3.15(2H, s), 1.22 (3H, t, J=7.1 Hz). Elementary analysis: Calculated forC₇H₁₂ClN₃O₄: C, 35.38; H, 5.09; Cl, 14.92; N, 17.68. Founded: C, 35.28;H, 5.02; Cl, 14.83; N, 17.68.

Example 6 Preparation of ethyl3-amino-2,5-dioxopyrrolidine-3-carboxylate

To a mixture of the compound of Example 5 (274 mg), acetic acid (10 ml)and water (5 ml) was added platinum oxide (25.5 mg) and the mixture wasstirred vigorously at 50° C. under hydrogen (atmospheric pressure) for 6hours. The reaction mixture was filtered through a Celite pad and theCelite was washed with a small amount of acetic acid. To the mixture ofthe filtrate combined with the washers was added sodium acetate (164 mg)and the mixture was concentrated. To the residue was added toluene toremove azeotropically the residual acetic acid and water and then themixture was concentrated again. To the residue was added ethyl acetateand the insoluble product was filtered off, and then the ethyl acetatesolution was concentrated to give the crude product and it was purifiedby a flash column chromatography (chloroform:methanol=30:1) to give thedesired product (122 mg, 66%) as crystal.

Example 7 Preparation of ethyl3-amino-2,5-dioxopyrrolidine-3-carboxylate

To a solution of the compound of Example 4 (970 mg) in dichloromethane(8 ml) was added trifluoroacetic acid (4 ml) and the mixture was stirredat room temperature for 6 hours. The reaction mixture was concentratedand to the resulting residue was added toluene to remove azeotropicallythe residual trifluoroacetic acid and then the mixture was concentratedagain. The residue was dissolved in ethanol (25 ml) and thereto wasadded an appropriate amount of Raney nickel. This mixture was stirredvigorously at 40° C. under hydrogen (atmospheric pressure) for 24 hours.To the reaction mixture was added water (20 ml) and the mixture wasfiltered through a Celite pad and then the Celite was washed withethanol. The mixture of the filtrate combined with the washers wasadjusted to pH 7-8 with sodium bicarbonate and then thereto was added pH7.4 phosphate buffer solution. This mixture was extracted with ethylacetate and the extract was dried over magnesium sulfate and filtered.The filtrate was concentrated to give an oil which was then purified bya flash column chromatography (chloroform:methanol=20:1→10:1) to givethe desired product (292 mg, 65%) as crystal.

Example 8 Preparation of (S)-(+)-camphorsulfonic acid salt of ethyl(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate

Ethyl 3-amino-2,5-dioxopyrrolidine-3-carboxylate (8.00 g) and(S)-(+)-camphorsulfonic acid (10.0 g) were dissolved in ethanol (80 ml)while warming, and this solution was concentrated under reduced pressureto about 45 ml in total. This solution was allowed to stand underice-cooling and precipitated crystal was collected by filtering andwashed with ethanol. This crystal was recrystallized from ethanol togive the desired product (4.70 g) as crystal.

Melting point: 229-230° C. (decomposition). [α]_(D) ²⁷+10.2° (c 1.03,MeOH).

¹H NMR (400 MHz, D₂O, 23° C.) δ: 4.43 (2H, q, J=7.2 Hz), 3.56 (1H, d,J=18.8 Hz), 3.28 (1H, d, J=15.2 Hz), 3.22 (1H, d, J=18.8 Hz), 2.86 (1H,d, J=14.8 Hz), 2.46-2.37 (1H, m), 2.16 (1H, t, J=4.8 Hz), 2.09-2.00 (1H,m), 1.84 (1H, d, J=18.8 Hz), 1.68-1.61 (1H, m), 1.49-1.42 (1H, m), 1.30(3H, t, J=7.2 Hz), 1.04 (3H, s), 0.83 (3H, s).

Example 9 Preparation of (S)-(+)-camphorsulfonic acid salt of ethyl(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate

To a solution of the compound of Example 1 (2.04 g) in acetic acid (30ml) was added platinum oxide (393 mg) and the mixture was stirredvigorously at 50° C. under hydrogen (atmospheric pressure) for 8 hours.During this reaction, to remove carbon dioxide generated with theprogress of the reaction, the gas in the reactor was replaced withhydrogen gas several times. The reaction mixture was filtered through aCelite pad and then the Celite was washed with a small amount of aceticacid. The filtrate combined with the washers was concentrated and to theresulting residue was added toluene to remove azeotropically theresidual acetic acid and then the mixture was concentrated again. To theresidue was added ethyl acetate and the insoluble product was filteredoff and then the ethyl acetate solution was concentrated to give thecrude product (918 mg). The crude product and (S)-(+)-camphorsulfonicacid (1.09 g) were dissolved in ethanol (40 ml) while warming and thissolution was concentrated under reduced pressure to 4-5 ml in total.This resulting mixture was allowed to stand at room temperature and theprecipitated crystal was collected by filtering and washed with ethanolto give the desired product (356 mg, 20%) as crystal.

Example 10 Preparation of ethyl(R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate(S)-(+)-Camphorsulfonic acid salt of ethyl

(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate (418 mg) was dissolved in25% aqueous acetic acid solution (4 ml). Thereto were added sodiumacetate (82 mg) and 2,5-dimethoxytetrahydrofuran (0.143 ml) and themixture was stirred at 70° C. for 1.5 hours. After allowed to cool, tothis mixture was added ethyl acetate (20 ml) and then the mixture werewashed with water, followed by saturated brine and dried over magnesiumsulfate and filtered. The filtrate was concentrated to give an oil. Thiswas purified by a flash column chromatography (hexane:ethyl acetate=3:1)to give the desired product (230 mg, 97%) as oil. ¹H NMR (CDCl₃) datawere consistent with those described in J. Med. Chem., 1998, 41, p. 4118to 4129.

¹H NMR (400 MHz, CDCl₃, 23° C.) δ: 9.05 (1H, br), 6.94 (2H, t, J=2.2Hz), 6.26 (2H, t, J=2.2 Hz), 4.28 (2H, q, J=7.2 Hz), 3.59 (1H, d, J=17.6Hz), 3.36 (1H, d, J=18.0 Hz), 1.26 (3H, t, J=7.2 Hz). ¹³C NMR (100 MHz,CDCl₃, 24° C.) δ: 172.7, 170.5, 166.8, 120.0, 110.1, 68.6, 63.9, 41.9,13.8. MS (APCI): 237(M+H).

Ethyl (R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate (220 mg)was dissolved in ethyl acetate (1 ml) and thereto was addeddiisopropylamine (0.130 ml). To this solution was added hexane (1 ml)and the resulting white suspension was warmed at 40° C. to give ahomogeneous solution. This mixture was allowed to stand at roomtemperature and precipitated crystal was collected by filtering to giveethyl (R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylatediisopropylamine salt (198 mg, 60%) as crystal.

Melting point: 80-85° C. ¹H NMR (400 MHz, DMSO-d₆, 22° C.) δ: 6.96 (2H,t, J=2.4 Hz), 6.01 (2H, t, J=2.2 Hz), 4.14-4.07 (2H, m), 3.27 (1H, d,J=17.2 Hz), 3.24-3.18 (2H, m), 2.98 (1H, d, J=17.2 Hz), 1.14 (12H, d,J=6.4 Hz), 1.13 (3H, t, J=6.8 Hz).

Example 11 Preparation of(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone

(1) To a solution of ethyl(R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate (767 mg) in ethylacetate (10 ml) was added trichloroacetyl chloride (1.1 ml) and thissolution was heated under reflux overnight. This reaction mixture wasallowed to cool to room temperature, and thereto was addedtrichloroacetyl chloride (1.1 ml) and this mixture was heated underreflux for 3 hours. This reaction mixture was allowed to water-coolingto room temperature and the residual trichloroacetyl chloride wasdecomposed carefully with saturated aqueous sodium bicarbonate solution.After the aqueous layer was confirmed to be alkali, this mixture wasextracted with ethyl acetate (5 ml) three times and the combined extractwas washed with water and saturated brine successively, dried overmagnesium sulfate, filtered and then concentrated to give a crudeproduct as oil. This was purified by a flash column chromatography(n-hexane:ethyl acetate=1:1) to give ethyl(R)-2,5-dioxo-3-(2-trichloroacetylpyrrol-1-yl)pyrrolidine-3-carboxylate(1.17 g, 94%).

¹H NMR (400 MHz, DMSO-d₆, 22° C.) δ: 12.4 (br s, 1H), 7.68 (dd, 1H,J=1.2, 4.4 Hz), 7.55 (dd, 1H, J=1.6, 2.8 Hz), 6.44 (dd, 1H, J=2.4, 4.4Hz), 4.25-4.08 (m, 2H), 3.72 (d, 1H, J=18.0 Hz), 3.06 (d, 1H, J=18.0Hz), 1.11 (t, 3H, 7.2 Hz).

(2) To a solution of 4-bromo-2-fluorobenzylamine (0.93 g) andtriethylamine (1.3 ml) in N,N-dimethylformamide (5 ml) was added asolution of ethyl

(R)-2,5-dioxo-3-(2-trichloroacetylpyrrol-1-yl)pyrrolidine-3-carboxylate(1.16 g) in N,N-dimethylformamide (3 ml) dropwise at room temperature.This mixture was stirred at room temperature for 8 hours. This reactionmixture was diluted with ethyl acetate, then washed with 1M hydrochloricacid (three times), water (four times), and saturated brinesuccessively, dried over magnesium sulfate, filtered and concentrated togive a crude product as yellow oil. This was purified by flash columnchromatography (n-hexane:ethyl acetate=2:1) to give(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone (831 mg, 65%). This product was furthercrystallized from n-hexane-ethyl acetate to give the desired product(385 mg) as crystal.

Mp: 189-191° C. ¹H NMR (400 MHz, DMSO-d₆, 22° C.) δ: 12.2 (br s, 1H),7.73 (dd, 1H, J=2.0, 3.2 Hz), 7.55 (dd, 1H, J=2.0, 9.6 Hz), 7.36 (dd,1H, J=2.0, 8.4 Hz), 7.17-7.12 (m, 2H), 6.53 (dd, 1H, J=2.8, 4.0 Hz),5.04 (d, 1H, J=15.2 Hz), 4.96 (d, 1H, J=15.6 Hz), 3.57 (s, 2H).

INDUSTRIAL APPLICABILITY

The present compound can be prepared in two or three steps from diethylmalonate as a starting material, and further it can be converted intothe compound of the formula (IV) as being a key intermediate oftetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives inone step. Additionally, the manufacturing process of the presentinvention does not require the use of hydrogen peroxide and also theyield of each step is high. Thus the compounds of the present inventionare useful as an intermediate oftetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives suchas Ranirestat being useful as a therapeutic agent for diabeticcomplications.

1-15. (canceled)
 16. A process for preparing2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising a step of preparing a3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate compound of formula (I)by process (A) or (B) below, and a step of converting the compound ofthe formula (I) into2′-(4-bromo-2-fluorobenzyl)spiro-[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof, (A) preparing a3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate of formula (Ia):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; wherein whenR¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkyl group; a C₃₋₈cycloalkyl group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, then R³ is atert-C₄₋₆ alkyl group; a 2,2,2-trichloroethyl group; or a benzyl groupin which the benzene ring moiety may be optionally substituted by one ortwo atoms or groups independently selected from the group consisting ofa halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano groupand a nitro group; when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a2,2,2-trichloroethyl group or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group and a cyano group, then R³ is a tert-C₄₋₆alkyl group or a 2,2,2-trichloroethyl group, by a process comprising astep of adding a compound of formula (III):R³OOC—N═N—COOR³  (III) wherein R³ is as defined above, to a compound ofthe formula (II):

wherein R¹ is as defined above, or (B) preparing a3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate of formula (Ib):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, by a processcomprising the following steps: (1) a step of undergoing ahydrogenolysis of the compound of the formula (Ia) above wherein R³ is abenzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a cyano group and a nitro group in the presence of apalladium catalyst; (2) a step of reacting the compound of the formula(Ia) above wherein R³ is a tert-C₄₋₆ alkyl group with an acid; or (3) astep of reacting the compound of the formula (Ia) above wherein R³ is a2,2,2-trichloroethyl group with zinc.
 17. The use of a compound offormula (I) in the manufacture of2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof.
 18. A use of a compoundof formula (I) in the manufacture of a medicament,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof.
 19. The use according toclaim 18 wherein R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkylgroup, R² is a hydrogen atom or a COOR³ group, and R³ is a tert-C₄₋₆alkyl group or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group, or a saltthereof.
 20. The use according to claim 18 wherein R¹ is a methyl group,an ethyl group, a propyl group or an isopropyl group, and R² is ahydrogen atom, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,or a salt thereof.
 21. The use according to claim 18, wherein thecompound of formula (I) is selected from the group consisting of ethyl3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,ethyl3-[N,N′-bis(tert-butoxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,and ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylatemonohydrochloride, or a salt thereof.
 22. The use of a compound offormula (I) in the manufacture of(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof.
 23. The use according toclaim 22 wherein R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkylgroup, R² is a hydrogen atom or a COOR³ group, and R³ is a tert-C₄₋₆alkyl group or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group, or a saltthereof.
 24. The use according to claim 22 wherein R¹ is a methyl group,an ethyl group, a propyl group or an isopropyl group, and R² is ahydrogen atom, a tert-butoxycarbonyl group or a benzyloxycarbonyl group,or a salt thereof.
 25. The use according to claim 22, wherein thecompound of formula (I) is selected from the group consisting of ethyl3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,ethyl3-[N,N′-bis(tert-butoxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,and ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylatemonohydrochloride, or a salt thereof.
 26. A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising using a compound of formula (I) as an intermediate or astarting material,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof.
 27. The process accordingto claim 26 wherein R¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆alkyl group, R² is a hydrogen atom or a COOR³ group, and R³ is atert-C₄₋₆ alkyl group or a benzyl group in which the benzene ring moietymay be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group,or a salt thereof.
 28. The process according to claim 26 wherein R¹ is amethyl group, an ethyl group, a propyl group or an isopropyl group, andR² is a hydrogen atom, a tert-butoxycarbonyl group or abenzyloxycarbonyl group, or a salt thereof.
 29. The process according toclaim 26 wherein the compound of the formula (I) is selected from thegroup consisting of ethyl3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,ethyl3-[N,N′-bis(tert-butoxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,and ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylatemonohydrochloride, or a salt thereof.
 30. A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising using a 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate offormula (I) or a salt thereof as an intermediate or a starting material,by preparing the 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate or asalt thereof by process (A) or (B) below,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; R² is ahydrogen atom or a COOR³ group; wherein when R¹ is a C₁₋₆ alkyl groupother than a tert-C₄₋₆ alkyl group; a C₃₋₈ cycloalkyl group; or an arylgroup or a heteroaryl group optionally substituted by one or two groupsindependently selected from the group consisting of a C₁₋₄ alkyl groupand a C₁₋₄ alkoxy group, then R³ is a tert-C₄₋₆ alkyl group; a2,2,2-trichloroethyl group; or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a 2,2,2-trichloroethylgroup; or a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a cyano group and a nitro group; when R¹ isa benzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group and a cyano group, then R³ is a tert-C₄₋₆ alkyl group or a2,2,2-trichloroethyl group, or a salt thereof, (A) preparing a3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate of formula (Ia):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group; wherein whenR¹ is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkyl group; a C₃₋₈cycloalkyl group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, then R³ is atert-C₄₋₆ alkyl group; a 2,2,2-trichloroethyl group; or a benzyl groupin which the benzene ring moiety may be optionally substituted by one ortwo atoms or groups independently selected from the group consisting ofa halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano groupand a nitro group; when R¹ is a tert-C₄₋₆ alkyl group, then R³ is a2,2,2-trichloroethyl group or a benzyl group in which the benzene ringmoiety may be optionally substituted by one or two atoms or groupsindependently selected from the group consisting of a halogen atom, aC₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a cyano group and a nitro group;when R¹ is a benzyl group in which the benzene ring moiety may beoptionally substituted by one or two atoms or groups independentlyselected from the group consisting of a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group and a cyano group, then R³ is a tert-C₄₋₆alkyl group or a 2,2,2-trichloroethyl group, by a process comprising astep of adding a compound of formula (III):R³OOC—N═N—COOR³  (III) wherein R³ is as defined above, to a compound ofthe formula (II):

wherein R¹ is as defined above, or (B) preparing a3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate of formula (Ib):

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group, by a processcomprising the following steps: (1) a step of undergoing ahydrogenolysis of the compound of the formula (Ia) above wherein R³ is abenzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a cyano group and a nitro group in the presence of apalladium catalyst; (2) a step of reacting the compound of the formula(Ia) above wherein R³ is a tert-C₄₋₆ alkyl group with an acid; or (3) astep of reacting the compound of the formula (Ia) above wherein R³ is a2,2,2-trichloroethyl group with zinc.
 31. A process for preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising a step of preparing a compound of formula (IV) and a step ofconverting the compound of the formula (IV) prepared in the precedingstep into(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group.
 32. A processfor preparing(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,comprising the following steps: (1) a step of preparing a compound offormula (IV); (2) a step of performing an optical resolution of thecompound of the formula (IV) prepared in the above step (1); (3) a stepof converting an amino group of the optically active compound preparedin the above step (2) (wherein the absolute configuration at carbon atomon 3 position of the dioxopyrrolidine ring of said compound is R) into1-pyrrolyl group; (4) a step of converting the pyrrolyl group of theproduct of the above step (3) into 2-trichloroacetylpyrrol-1-yl group;and (5) a step of reacting the product of the above step (4) with4-bromo-2-fluorobenzylamine to convert it into(3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2H′)-tetraone,

wherein R¹ is a C₁₋₆ alkyl group; a C₃₋₈ cycloalkyl group; a benzylgroup in which the benzene ring moiety may be optionally substituted byone or two atoms or groups independently selected from the groupconsisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy groupand a cyano group; or an aryl group or a heteroaryl group optionallysubstituted by one or two groups independently selected from the groupconsisting of a C₁₋₄ alkyl group and a C₁₋₄ alkoxy group.
 33. Theprocess according to claim 30 wherein the3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate is a compound wherein R¹is a C₁₋₆ alkyl group other than a tert-C₄₋₆ alkyl group, R² is ahydrogen atom or a COOR³ group, and R³ is a tert-C₄₋₆ alkyl group or abenzyl group in which the benzene ring moiety may be optionallysubstituted by one or two atoms or groups independently selected fromthe group consisting of a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a cyano group and a nitro group, or a salt thereof. 34.The process according to claim 30, wherein the3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate is a compound wherein R¹is a methyl group, an ethyl group, a propyl group or an isopropyl group,and R² is a hydrogen atom, a tert-butoxycarbonyl group or abenzyloxycarbonyl group, or a salt thereof.
 35. The process according toclaim 30, wherein the 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylate isselected from the group consisting of ethyl3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,ethyl3-[N,N′-bis(tert-butoxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate,and ethyl 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylatemonohydrochloride, or a salt thereof.